NFκB exists as a dimer formed by various combinations of p50, p65/RelA, c-Rel, Rel-B, and p52, all of which are members of the NFκB family. Among them, the most well-known dimer is a heterodimer composed of a 50 kDa subunit (p50) and a 65 kDa subunit (p65).
Usually, this heterodimer is present in an inactive state in cytoplasm through binding to an inhibitor of NFκB (IκB). However, once the cells are stimulated by inflammatory cytokines, cell growth factors, and the like, IκB kinase is activated via the AKT signal transduction pathway and the like, leading to phosphorylation of IκB. The phosphorylated IκB is ubiquitinated and then decomposed by proteasome. As a result, NFκB is detached from IκB and migrate into the nucleus, where it binds to the NFκB responsive element to activate transcription of various target genes.
The target genes include many genes associated with inflammation and immune response (Non Patent Document 1), and the activation of NFκB is known to be associated with diseases such as rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, atopic dermatitis, and asthma (Non Patent Document 2).
Also, various viruses such as HIV are known to activate NFκB in host cells, from which NFκB is considered to contribute to viral infection (Non Patent Documents 3 and 4).
Furthermore, recently, NFκB is known to be often constitutively activated in various tumors, and thus it is considered that NFκB may possibly be involved also in the induction of expression of various genes associated with the progression of cancer, such as carcinogenesis, metastasis, anti-apoptosis, and cell proliferation, and the resistance against anticancer agent therapy (Non Patent Documents 5 and 6).
Further, NFκB is also known to be associated with diseases such as ischemic heart disease (Non Patent Document 7), Alzheimer's disease (Non Patent Document 8), ichorrhemia (Non Patent Document 9), and metabolic syndrome (Non Patent Document 10).
Accordingly, a compound inhibiting NFκB is useful as a preventive or therapeutic agent for chronic inflammatory disease, autoimmune disease, viral disease, immune disease, novel cancer therapy, and other diseases attributable to the activation of NFκB, and such a compound is actively developed.
Meanwhile, tylophorine represented by the following formula (A) and an analog thereof are called phenanthroindolizidine alkaloid, which is a compound mainly obtained from a plant belonging to the family Asclepiadaceae (the genera Tylophora, Vincetoxicum, Pergularia, and Cynanchum) (Non Patent Document 11).
Also, some of the aforementioned plants belonging to the genus Tylophora are known as raw materials for anti-inflammatory drugs, antiasthma drugs, and antiameba drugs (Non Patent Document 12). Also, tylophorine is known to exhibit a potent cytotoxic activity, and a research on the synthetic method thereof is also vigorously conducted (Non Patent Document 13). Further, among the above-noted phenanthroindolizidine alkaloid, tylocrebrine represented by the following formula (B) is known to have neurotoxicity (Non Patent Document 14). Also, recently, it is known that tylophorine analogs represented by the following formulas (C) and (D) have consistently exhibited a potent cytotoxic activity in the NCI-60 tumor cell panel study, and that the mechanism of action of those tylophorine analogs is different from that of existing antitumor agents (Non Patent Document 15). Further, a compound represented by the following formula (E), which is phenanthroindolizidine alkaloid derived from the insect, is known to have a potent cytotoxic activity (Non Patent Document 16).
Furthermore, phenanthroindolizidine alkaloid is known to inhibit transcription mediated by NFκB, which is a transcription factor (Non Patent Document 15).
